Method for producing a storable molded body made of bacterial cellulose and a molded body produced according to the method

ABSTRACT

The invention relates to a method for producing a storable molded body made of bacterial cellulose and a molded body produced according to the method. A preferred method includes providing a molded body made of bacterial cellulose. Optionally, mechanically pressing the entire molded body or parts of the molded body at temperatures in the range of 10° C. to 100° C. and pressures in the range of 0.01 to 1 MPa for a pressing time of 10-200 min. Treating the molded body with a solution of 20% by weight to 50% by weight of glycerol and 50% by weight to 80% by weight of a C1-C3-alcohol/water mixture. Drying the treated molded body.

TECHNICAL FIELD

The invention relates to a method for producing a storable molded bodymade of bacterial cellulose and a molded body produced according to themethod. The invention also concerns materials for medical implants andmedical implants.

BACKGROUND

In the field of modern medical technology, highly diverse types ofmaterials are used as implant materials. The substance characteristicsof these materials that are decisive for the particular field ofapplication are, in particular, the biocompatibility and mechanicalproperties of these materials. Bacterial cellulose is a promisingbiocompatible material.

Bacterial cellulose is an extracellular metabolic product formed bymicroorganisms and has properties that are comparable to those ofplant-based cellulose. The purity is significantly higher, however,since there are no foreign polymers or other inclusions containedtherein.

The supramolecular structure thereof gives bacterial cellulose a highlyhydrophilic character, high absorbing capacity and mechanical strength.Of all cellulose-forming microorganisms, the gram-negative aerobicspecies Gluconacetobacter xylinus, formerly also known as Acetobacterxylinum is of particular significance.

Disadvantageously, however, the mere dehydration and renewed hydrationof the cellulose results in a distinct loss of volume. Moreover,conventionally dehydrated cellulose is very brittle. As a result,conventional implants that comprise bacterial cellulose in entirety orin parts cannot be stored.

SUMMARY

One or more of the aforementioned problems associated with the prior artcan be eliminated or at least ameliorated by methods of the invention,for producing a storable molded body made of bacterial cellulose. Apreferred method includes the steps of:

-   i) providing a molded body made of bacterial cellulose;-   ii) optionally, mechanically pressing the entire molded body or    parts of the molded body at temperatures in the range of 10° C. to    100° C. and pressures in the range of 0.0005 to 1.5 MPa, preferably    0.01 to 1 MPa for a pressing time of 10-200 min;-   iii) treating the molded body with a solution of-    20% by weight to 50% by weight of glycerol and 50% by weight to 80%    by weight of a C1-C3-alcohol/water mixture; and-   iv) drying the treated molded body.

The invention also provides a storable molded body made of treatedbacterial cellulose, wherein the treated bacterial cellulose is dry andhas a swelling capacity that is greater than untreated bacterialcellulose of the same type.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is explained in greater detail in the followingwith reference to drawings and embodiments. In the drawings:

FIG. 1 shows a first embodiment of the molded body according to theinvention, in the form of an implant shell for a pacemaker;

FIG. 2 shows a side view of a further embodiment of the molded bodyaccording to the invention, in the form of a heart valve prosthesis;

FIG. 3 shows a top view of the heart valve prosthesis in FIG. 2;

FIG. 4 shows a simplified representation of a stent structure with stentstruts and nodal points.

FIG. 5 shows a view of a section of a stent structure wherein stripes ofbacterial cellulose are running above and below the stent struts.

FIG. 6 shows a view of a section of a stent structure wherein strips ofbacterial cellulose are running above and below the stent struts.

FIG. 7 shows a further embodiment of the molded body according to theinvention, in the form of a stent graft;

FIG. 8 shows a further embodiment of the molded body according to theinvention, in the form of a stent;

FIG. 9 shows a schematic depiction of a culture vessel, with whichbacterial cellulose having different material-layer thicknesses can beseparated out;

FIG. 10 shows a comparative depiction of the NF-kB activity in THP-1cells; and

FIG. 11 shows a top view and a side view of sections of a strutcomprising a plurality of barbs.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Preferred methods of the invention provide a molded body made ofbacterial cellulose, in particular bacterial cellulose fromGluconacetobacter xylinus, that has been treated according to theabove-described drying process, that is now storable, since thebacterial cellulose is no longer brittle, due to the drying, as is thecase with conventional drying processes. The cellulose can now beprocessed and stored in the dry state without losing the positivecharacteristics of the material. It was shown, for example, that theanti-inflammatory properties and good biocompatibility are retained, asis the high mechanical strength as well as the swelling capacity of thematerial. The swelling capacity can be set to different levels byapplying different pressure levels to different parts of the moldedbody, as well as by pressing different parts of the molded body.

The bacterial cellulose is initially provided in a form that is suitablefor the subsequent application. For example, layers of bacterialcellulose are separated out of nutritive solutions, which containglucose and were inoculated with Gluconacetobacter xylinus, in a mannerknown per se, and are then air-dried. It is also conceivable that acovering of high-purity cellulose fibers is allowed to grow directly ona carrier material, for example the metallic base body of a stent.

A newly developed culture vessel has made it possible to produce layersof bacterial cellulose having different material thicknesses. To thisend, the culture vessel comprises a gas-permeable silicone layer, thethickness of which varies, and which is in contact with the culturesolution to be accommodated in the culture vessel. In regions of reducedthickness of the silicone layer, more air diffuses to the boundary layerbetween the culture solution and the silicone layer, with the resultthat the aerobic bacterial growth is increased in this region, andtherefore cellulose deposits here to an increasing extent. Layers ofbacterial cellulose can be produced in this manner, for example, thathave a layer thickness that varies in the range of 2 to 10 mm.Consequently, it is possible to provide suitable implantation materialwith a higher thickness than natural material of human or animal originsuitable for the preferred applications as prosthetic material for heartvalves.

Additional preparatory measures may be required to provide the requiredmolded body of bacterial cellulose, such as purification, pressing,pre-drying, assembly, and cutting the material into the required shapeand size.

Bacterial cellulose which is to be used for medical implants calls for ahigh standard in terms of purity, particularly related to pyrogenicmolecules. The layers of bacterial cellulose can contain residualbacteria, which may not be efficiently removed by conventional methodssuch as washing in aqueous alkaline solution (DE 40 27 479 A1, U.S. Pat.No. 4,588,400 A) and use of detergents, such as sodium dodecyl sulfate(SDS, EP 1 660 670 A). Therefore, in a preferred embodiment the firststep i) of the inventive method comprises the sub-steps of:

-   -   a) transferring the body of bacterial cellulose into an aqueous        solution of 1-10% by weight of at least one surfactant and        0.4-4% by weight of at least one base,    -   b) treating the body of bacterial cellulose by means of        microwaves at a temperature of at least 80° C., but less than        100° C., for 30-60 min,    -   c) washing the body of bacterial cellulose in a solution of        aqueous weak acid in combination with application of microwaves,        and rinsing with water.

In the sub-steps a) and b) any bacteria present yet in the cellulosematerial are killed by the alkaline surfactant solution and quicklylysed by the microwave radiation. Consequently the bacteria areefficiently killed and destroyed. The washing sub-step c) facilitates aneutralization of the bacterial cellulose as well as a quick removal ofbacterial particles, including any endotoxins and/or pyrogenic remnants.Furthermore the inventive method is faster and works with milderdetergents than conventional methods of cleaning bacterial cellulose.Consequently the embodiment is advantageous because they allow aparticular efficient production of bacterial cellulose which is free ofpyrogens.

The concentration of the surfactant is preferably 1-10% by weight, morepreferred 2-8% by weight, more preferred 3-6% by weight, andparticularly preferred 4% by weight. The concentration of the at leastone base is preferably 0.4-4% by weight, more preferred 0.6-3% byweight, more preferred 0.8-2% by weight, and particularly preferred 1%by weight.

Suitable bases can be selected from the group comprising or consistingof alkali and earth alkali hydroxide such as sodium hydroxide, potassiumhydroxide, alkali and earth alkali carbonates, alkali and earth alkalihydrogencarbonate, ammonia and triethyl amine.

Anionic, nonionic and zwitterionic surfactants can be used in theinvention. It is also possible to use a combination of surfactants.Anionic surfactants to be used comprise sodium cholate, sodiumdeoxycholate, sodium glycocholate, sodium taurodeoxycholate, taurocholicacid, N-lauroylsarcosine, and sodium dodecyl sulfate. Nonionicsurfactants to be used compriseN,N-Bis(3-(D-gluconamido)-propyl)deoxycholamide, digitoin, saponins,polidocanol, Dodecyldimethyl-phosphine oxide, Dimethyldecylphosphineoxide, Octyl-b-glucopyranoside, Decyl-b-maltopyranoside,decyl-b-1-thiomaltopyranoside, octyl-b-1-thioglucopyranoside,undecyl-b-maltoside, n-dodecyl-b-maltoside,6-cyclohexylhexyl-b-maltoside, Triton-X-100, Triton-X-140, Tween 20,Tween 80, NP-40, Brij-35, Brij-58, octyl glucoside, octyl thioglucoside,and surfactin. Zwitterionic surfactants to be used comprise ASB-14,ASB-16, C7BzO, CHAPS, CHAPSO, EMPGEN BB.

The temperature in sub-step b) shall not rise above 100° C. because thesolution is not supposed to boil, which could lead to the evolution ofgas causing damage to the bacterial cellulose. Within the preferredtemperature window of 80 to 100° C., it is more preferred if thetemperature is between 85 and 95° C., and yet more preferred if thetemperature is around 90° C. The energy level and timing of themicrowave radiation is set to a point which allows controlling thetemperature in said temperature window.

The washing with weak acid such as acetic acid, oxalic acid orphosphoric acid, in sub-step c) serves for neutralization of thebacterial cellulose after the treatment with the alkaline solution instep b). Alternatively to weak acids such as acetic acid, dilutedhydrochloric acid, nitric acid or sulfuric acid and the like can be usedfor washing. Instead of microwaves, vacuum filtration can be applied tosupport the washing in sub-step c).

It is particularly preferred if after sub-step b) an additional sub-stepis to be performed:

-   -   b′) incubating the body of bacterial cellulose in an enzymatic        solution of at least one lytic enzyme at about 37° C. for at        least 15 min.

The enzymatic treatment step b′ is advantageous because any residualbacteria yet present in the bacterial cellulose are lysed. The termlytic enzyme as used in this description refers to any enzyme which canbe used for the lysis of bacteria and digestion of bacterial molecules.

Preferred enzymes are achromopeptidase, lysozyme, and amylase. It ispossible to use one single enzyme in sub-step b′), as well as acombination of two enzymes, or a combination of three or more enzymes.The temperature and time of incubation can be varied depending on theenzymes. The enzymes are inactivated and removed by the washing andapplication of microwaves, or vacuum filtration, in sub-step c).

In the optional step ii) of the inventive method, the entire molded bodyor parts of the molded body are mechanically pressed at temperatures inthe range of 10° C. to 100° C. and pressures in the range of 0.0005 to1.5 MPa, preferably 0.01 to 1 MPa for a pressing time of 10-200 min.

A further preferred embodiment of the inventive process provides that inthe second step ii) of the process the temperature is preferably in therange from 80° C. to 100° C. and the pressure is preferably in the rangefrom 1.5 MPa to 2 MPa. In a different embodiment the pressure can bepreferably in the range from 1.0 to 10 kPa and more preferably 1.5 kPato 2 kPa at a temperature range of 80° C. to 100° C. The primary goal ofthe so-called hot pressing is to remove water present in the bacterialcellulose completely, or at least partially. The pressing isadvantageous, because as a result of the pressing the swelling capacityof the cellulose is reduced and can be set to a desired level.Furthermore the mechanical stability of the cellulose is increased.However, the pressure shall not be too strong to avoid mechanical damageof the material or destruction in form of cutting or crushing.

In step iii) of the method according to the invention, the molded bodythat is made of bacterial cellulose and is required for the particularapplication is then washed with the C1-C3 alcohol/water mixture (forexample, methanol, ethanol, 1-propanol and 2-propanol) and glycerol, inparticular in a special isopropanol/water solution containing glycerol,or is incubated in the solution. The solution contains between 20% byweight and 50% by weight of glycerol. The remainder is formed by theC1-C3 alcohol/water mixture. The ratio of C1-C3 alcohol to water in theC1-C3 alcohol/water mixture is preferably between 90 to 10 and 70 to 30.Particularly preferred is a C1-C3 alcohol/water mixture of 80% by weightof C1-C3 alcohol, in particular isopropanol, and 20% by weight of water.The portion of water in the incubation solution of glycerol and C1-C3alcohol/water mixture preferably does not exceed 20% by weight. Thesolution can contain further components, but is preferably limited tothe aforementioned three components. The time period of the incubationin the solution is typically 0.5 to 24 h, and preferably 12 h.

Next, the molded body to be treated with the solution is dried. Thedrying can be carried out as air-drying (1 to 2 days). By air-drying atroom temperature (typically 20-25° C.) the alcohol and a major part ofthe water are removed from the cellulose. The drying can also be carriedout under vacuum or in a climatic chamber. After drying the bacterialcellulose can still contain glycerin with a content between 0.1 and 10%by weight, with an indicative value of 1.5% by weight. Due to thehygroscopic nature of glycerin it is possible that there is still waterpresent in the bacterial cellulose.

Within the scope of the invention, a molded body is intended to mean aphysical object having any possible shape. In the simplest case, thiscan be a virtually two-dimensional, flat object (similar to a materialstrip). This is also intended to mean more complicated,three-dimensional shapes such as cylindrical tube sections up to morecomplex shapes, for example heart valves.

The bacterial cellulose treated using the method according to theinvention can now be stored, wherein the desired anti-inflammatoryproperties and the compatibility of the material are retained. For thecase in which the optional step ii) is omitted, the bacterial cellulosesurprisingly exhibits a swelling capacity that is clearly increased ascompared to the non-treated starting material.

Consequently, a further aspect of the invention is related to a moldedbody made of bacterial cellulose, which is storable and, optionally, hasswelling capacity, and which was produced using the above-describedmethod.

Furthermore, it has been shown that the swelling capacity of cellulosecan be influenced in a targeted manner by means of the method accordingto the invention. The invention is based on the finding, in particular,that dried bacterial cellulose, in particular bacterial cellulose fromGluconacetobacter xylinus, can be completely rehydrated by means of thespecial drying process and contrary to previous expert opinion, and thewater absorbance capacity can be increased even further by means of thedrying process if the optional step ii) is omitted.

The swelling capacity of the entire molded body or parts of the moldedbody can therefore be adapted to the requirements for the particularapplication by means of the mechanical pressing in step ii). In otherwords, regions of one and the same molded body can be variedindependently of one another in terms of swelling capacity. The moldedbody has preferably at least one region with a reduced swelling capacitybased on mechanical pressing in relation to an adjacent region of thebody.

A further aspect of the invention is related to an implant comprisingthe aforementioned molded body in entirety or in parts. In other words,the molded body itself can be the implant or is merely one componentthereof.

According to one first variant, the molded body is therefore an implantshell. A layer that closes off the entire implant or essential parts ofthe implant toward the outside therefore comprises the treated bacterialcellulose. The implant shell can be a type of bag or pocket, forexample, in which the further components of the implant are located. Thevery good biocompatibility of the bacterial cellulose preventscomplications due to rejection reactions, which is a particularlyimportant aspect when the implant is a cardiac pacemaker ordefibrillator stored in the implant shell. The implant shell preferablyadditionally comprises a separate pocket for accommodating overhangingelectrode cables.

EP 2 484 406 A1 and U.S. Pat. No. 7,454,251 describe devices that makeit possible to roll up, in a defined manner, an overhanging electrodecable in pacemakers. This rolling-up does not prevent a tissue capsulefrom forming on the implant, however.

The biocompatible enclosure of the implant makes it possible to preventmassive fibrotic tissue regeneration. In addition, eventual explantationis simplified. The implant shell can also comprise a separate pocket foroverhanging electrode leads that may be present.

The implant shell can be produced, for example, in such a way thatlayers of the treated bacterial cellulose are sutured with a surgicalsuture. The pacemaker or defibrillator can be packaged in the implantshell, which is rehydrated with a sterile (isotonic) saline solution,shortly before implantation. By means of the implant shell, it is alsopossible to prevent the electrodes from adhering too strongly in theregion of the unit, thereby ensuring that the unit can be more easilyreplaced. The anti-inflammatory effect of the bacterial cellulosegreatly reduces the risk of infection. Optionally, the material of theimplant shell can also be a drug carrier, for example for the temporaryrelease of antibiotics, such as rifampicin, minocycline, doxycyline,tetracycline, gentamycin, vancomycin, linezolid and tigecycline,anti-inflammatory agents, such as paclitaxel, prednisolone,dexamethasone, rapamycin, tacrolimus and ciclosporine, growth factors,for example EGF, HGF, TGF, PDGF, VEGF, NGF and G-CSF and cytokines, forexample IL-1B, IL-8. A further aspect of the material is that it can beprocessed dry, sterilized, and then stored for months. In our owntrials, it was confirmed that the material retains the very goodanti-inflammatory properties thereof even after the special drying.

According to a second variant, the molded body is a component of a heartvalve prosthesis, in particular a heart valve leaflet and/or a sealingshell (skirt) between the heart valve leaflets and the stent base bodyof the heart valve prosthesis. Formed bodies made of bacterial cellulosethat have been treated according to the method are therefore suitablefor the production of the essential functional components of a heartvalve prosthesis. In contrast to conventional heart valves leaflets,which are formed from pericardium, for example, the heart valvesaccording to the invention can be stored in a dry, sterilized manner anddo not need to be rehydrated until shortly before implantation.Moreover, the suture diameter, suture thickness and the orientationthereof, the layer thickness and homogeneity of the valve leaflet can beindividually set by adjusting the culture conditions or byafter-treatment. In other words, the material according to the inventionmakes it possible to create heart valve prostheses that areindividualized and, therefore, substantially more compatible. The heartvalve prosthesis can be delivered in a fully pre-assembled state and notwith the insertion device and the valve itself delivered separately, asis currently the case with conventional prostheses. Due to the use ofcellulose, the size of the device can be drastically reduced overall(from the current size of 18 Fr to 12 to 14 Fr).

Bacterial cellulose pretreated according to step ii) is used for theheart valve leaflet. In addition to the heart valve leaflets, thematerial can also be used, in particular, for sealing between the nativeheart valve leaflet and the stent base body, in this case in the form ofan inner and/or outer peripheral shell made of the material. The radialseal relative to the vessel wand is greatly improved due specifically tothe significantly improved swelling capacity of the material. Currentmaterials used in skirts are not made of materials with swellingcapacity, wherein the intention is to seal paravalvular leaks at theskirt by overhanging the material (see, for example, US 2013/0018458A1). This cannot always be ensured, however, due to the high pressuregradients at the transition from the ventricle to the atrium. Inaddition, the material that is used poses a risk of inflammation withthe associated risk of contamination by bacteria that can triggerendocarditis. The material according to the invention has the propertyof storing a great deal of water and, in contrast to a hydrogel, ofreleasing this water in response to mechanical loading. Due to thisparticular elastic sealing property, paravalvular leakage is prevented,wherein the skirt made of treated bacterial cellulose—as compared toother materials—can be very thin (preferably 0.05 to 0.2 mm) and canhave a swelling ratio of min. 1:10. Consequently, the skirt is providedfor preventing paravalvular leakage. Herein paravalvular leakages areleakages with the risk of streaming blood leaking between the implantand the wall of the vessel or the heart valve. The skirt is disposed atthe luminal and/or abluminal section of the stent base body of the heartvalve implant. The luminal section of the stent base body comprisesparticularly the inner side of the stent, whereas the abluminal sectioncomprises the outer side of the stent. The skirt can comprise sectionsor partial sections which are not consisting of bacterial cellulose asdescribed herein, but of other materials. It is however also possible,that the entire skirt consists bacterial cellulose, as described herein.If an embodiment of the skirt comprises sections of other materials thanbacterial cellulose, then the skirt comprises at least one molded partof bacterial cellulose, as well, which has been treated by the inventivemethod. The reduced swelling capacity of the molded body is ideallyaffected by the inventive method, namely the mechanical pressing in stepii).

In an embodiment of the inventive heart valve implant the skirt has areduced swelling capacity in the luminal section and at least partiallyincreased swelling capacity in the abluminal section. In a furtherembodiment of the inventive heart valve implant the skirt is disposed atthe luminal side of the stent base body. At least one molded body,preferably a number of molded bodies, is disposed, preferably sewn in,between the stent struts and the skirt. The at least one molded body isformed of bacterial cellulose produced by the inventive method andincludes sections with an increased swelling capacity. The at least onemolded body with an increased swelling capacity is preferably disposedbetween the stent base body and a skirt made of material with noswelling capacity, wherein the increase of the volume of the swellingmolded body is directed radially outwards. The luminal skirt can be madeof bacterial cellulose or of other materials, mainly with no swellingcapacity, such as polymers, other artificial materials or biologicalmaterial such as pericard or lung, stomach or gut tissue.

The at least one molded body is preferably disposed between a nodalpoint of the stent strut structure and the luminally disposed skirt.Preferably a number of molded bodies are disposed adjacent to eachother, so that an annular ring is formed in circumferential direction ofthe skirt. At least one molded part is sewn to the stent strutstructure, preferably to the stent struts, and to the nodal points ofthe stent strut structure, as well. The term nodal point refers topositions of the stent structure where the struts are connected to eachother. Ideally the edges and brinks of the molded part are running atleast partially on the struts of the stent base body.

The skirt is preferably disposed in the luminal section of the stentbase body and has a reduced swelling capacity in the sections disposedbelow the struts of the stent base body. It is further preferred if theskirt is disposed luminally at an end of the stent base body which islocated in proximity to a heart valve and the inflow region of thevalve, respectively.

Furthermore the skirt is preferably disposed in the luminal andabluminal sections of the stent base body and is laced in form of atleast one ribbon around the struts of the stent base body in analternating fashion. The ribbon has a reduced swelling capacity in thesections disposed below the struts of the stent base body.

In general, the use of bacterial cellulose according to the methodaccording to the invention in heart valve prostheses has manyadvantages:

-   -   The valve leaflet and/or the skirt can be processed dry.    -   The heart valve prosthesis produced in this manner can therefore        be shipped in a dry, preassembled state and can be stored for a        long period of time.    -   Moreover, the risk of calcification of such a heart valve        prosthesis is less, since, in contrast to the prior art,        biological tissue prepared with glutaraldehyde is not used for        the valve leaflet in this case.    -   Furthermore, the heart valve prosthesis has a lower risk of        inflammation due to the antibacterial properties of the        bacterial cellulose.

Percutaneously implantable heart valve prostheses, for example for themitral valve, have a metallic base body, which is used for anchoring atthe implantation site and carries the artificial heart valve leaflet.For example, US 2011/0208298 A1 describes a holding device, which clampsa percutaneous mitral valve between the mitral annulus and the distalend of the natural valve leaflet by means of two clip structures. U.S.Pat. No. 8,252,051 describes a percutaneous mitral valve, in whichadditional holding structures, in the form of hooks, are mounted on thestent base body. These outwardly bent, hook-shaped projections engageinto the surrounding tissue and thereby anchor the valve in the tissuein order to prevent proximal dislocation.

Disadvantages of the aforementioned solutions are the fact that the clipand hook structures do not permit the valve to be small and compact.Therefore, in the aforementioned embodiment of the prior art, forexample, it is necessary to lengthen the valve on the distal end to theextent that the clip structure protrudes beyond the distal end of thenatural valve leaflet. In addition, the clip structure necessitates alarger diameter of the curved valve, which cannot be minimized further.The holding structures in the form of hooks in U.S. Pat. No. 8,252,051 Bcan damage the aortic valve or the Ramus circumflexus if tissuepenetration is too deep or due to implant erosion. As is the caseaccording to the invention, however, if the molded body comprises barbson an outer side of the stent base body thereof, an adhesive connectionfor preventing dislocation of the valve can be ensured without theaforementioned disadvantages.

The barbs preferably have a length of <0.5 mm, in particular a length inthe range of 0.1 to 0.3 mm.

A further aspect of the invention relates to a catheter comprising aheart valve prosthesis, which has at least one molded body made ofbacterial cellulose according to the method according to the invention,wherein the heart valve prosthesis is mounted on the catheter in thedried state.

According to a third variant, the molded body is an outer shell and/oran inner shell of a stent graft made of bacterial cellulose according tothe method according to the invention. The bacterial cellulose treatedaccording to the invention is therefore also suitable for producing aself-sealing stent graft. According to the prior art, endovascular stentgrafts are implanted with an exact fit, for example into the aorta, inorder to treat aneurysms. In ten to forty percent of cases, theseexhibit leakage, with the risk of the aneurysm rupturing. A significantportion of these patients exhibit leaky points at the transition of thenative aorta to the stent graft.

These so-called type I leaks are caused by the graft slipping or are dueto the individual anatomy.

A method that is intended to solve this problem is described in US2013/0197622 A1. In this case, a swellable hydrogel is placed in a cuffabout the distal or proximal end of the stent graft, which swells aftercoming into contact with moisture or after addition of a foaming agent.The use of hydrogels has the disadvantage, however, that these must beenclosed with an additional membrane. In addition, the biocompatibilityand long-term mechanical stability of the material is questionable.Finally, reversible swelling is not possible.

If outer and/or inner shells of the stent graft are formed of thebacterial cellulose treated according to the invention, however, amaterial is then available that is reversibly swellable, biocompatible,and non-degradable, and avoids all the aforementioned disadvantages. Ithas been shown that bacterially synthesized cellulose is particularlysuitable therefor. This can be synthesized by Gluconacetobacter xylinusin tubular form by the metabolization of a glucose-containing nutritivesolution and can then be specially dried. The high-purity cellulosefiber tubes that are formed have mechanical properties, in the moiststate, that are similar to those of blood vessels and can easilywithstand pressures of 120 mm of mercury. For production, a fleece madeof the cellulose is sutured with a stent, or the fleece is generatedintegrally with the stent.

According to a preferred embodiment, the inner or outer shell comprisesannular sections, which are disposed on the axial ends of the stentgraft and exhibit a greater swelling capacity than do sections of theshells located between the two ends. In other words, the swellingcapacity is increased at the two ends of the stent graft, for example byincreasing the layer thickness, and/or the center sections of the shellwere pretreated as described in step ii) of the method. After thecellulose is moistened, the shells are thickened at the two ends andthereby close any leakages that may occur at the distal and proximal endof the stent graft. The other sections of the inner or outer shell donot swell, since the layer thickness is thinner or due to a modifieddrying scheme (step ii), or do not swell to the same extent, and formthe tube-like blood vessel replacement. The material for the inner andouter sleeve can be processed in the dried state and is very thin, andcan therefore be used for stent grafts and with a particularly smalldiameter. Microstructuring can be implemented on the luminal side inorder to accelerate the re-endothelialization. This can be impressedwith a dimension of 1 to 10 μm directly in the synthesis of thebacterial cellulose layer (see also US 2012/0053677 A1).

According to a fourth variant, the molded body is a covering of a stent.According thereto, the material according to the invention is used toproduce a stent that is covered by a biocompatible fleece comprisingbacterial cellulose.

Such a stent graft comprising a fleece made of bacterial celluloseand/or having annular sections made of bacterial cellulose having anincreased swelling capacity has a number of advantages:

-   -   When annular sections made of swellable bacterial cellulose are        used, a good form-fit connection between the vessel wall and the        stent graft is obtained.    -   Due to the use of a fleece made of bacterial cellulose, the        biocompatibility of the stent graft is increased and the        potential for inflammation is reduced due to the antibacterial        properties of the cellulose.    -   The structured surface of the fleece made of bacterial cellulose        promotes good re-endothelialization.    -   Moreover, a stent graft comprising a fleece made of bacterial        cellulose can be compressed to a small diameter. The stent graft        can therefore be gently brought to the implantation site using a        catheter having a relatively small outer diameter, and can be        implanted there.

So-called covered stents comprise a stent base body covered with apolymer (e.g., polyurethane or polytetrafluorethylene), which isstretched between the stent struts as a membrane or by means ofhot-embossing, or is applied by means of electrospinning (see, forexample, EP 2 380 526 A2 or EP 0 866 678 B1). In addition, it is knownthat bacterial cellulose produced by fermentation is suitable for use asfleece for covering stents. In this case, the cellulose is depositeddirectly between the stent struts in a special bioreactor (see EP 1 569578 B1). A disadvantage of the use of polymer films is greatly reducedbiocompatibility and an increased risk of inflammatory reactions.Bacterial cellulose, on the other hand, is highly biocompatible, but isvery brittle in the untreated, dried state and can become damaged duringthe crimping process.

It has been shown, surprisingly, that the above-describedafter-treatment with an alcoholic glycerol solution imparts bacterialcellulose with mechanical properties in the wet state that are similarto those of the natural vessel wall. Moreover, it has been shown thatthe swelling behavior of the bacterial cellulose can be controlled byimmersion in diluted alcoholic glycerol solutions. The treated bacterialcellulose is also no longer brittle and can be processed, by squeezing,to form a very thin cellulose fleece, which can be placed tightly aroundthe stent frame. This thin membrane, in the dried state, requires onlythat the implant be thickened to a negligible extent and therebysimplifies implantation. In addition, it has been shown that the specialafter-treatment with glycerol imparts flexibility to the cellulose,thereby enabling the cellulose to be folded during crimping. After theimplant is moistened, the cellulose swells to an adjustable thicknessand thereby forms an extremely tension-resistant, highly hydratedfleece, which permits repopulation with endothelial cells and issimultaneously pressure-tight. Moreover, the bacterial cellulose reducesthe risk of an inflammatory reaction and is biocompatible. In order toaccelerate re-endothelialization, microstructuring of the luminal sidecan be implemented, as described above.

According to a fifth variant, the molded body is a vascular patch.According to the prior art, patches for covering relatively extensivevascular damage are woven out of plastic, such as polyester, or are castof polytetrafluorethylene. In addition, the woven structures areadditionally sealed with collagen in order to prevent leakage caused bythe web structure.

This results in the disadvantage that the seal integrity of seams cannotbe ensured with PTFE, and, with polyester, biocompatibility is reducedand the susceptibility to inflammatory reactions is therefore increased.

According to a further variant, the molded body is an occluder, which isimplanted in the heart by means of a catheter in order to treat/close apatent foramen ovale. Such an occluder has the shape of a small umbrellaand closes the patent foramen ovale.

According to a further variant, the molded body is an artificial tendon.

The bacterial cellulose treated according to the invention thereforeprovides an easily swellable, self-sealing, and biocompatible materialfor producing an improved vascular patch or material for use in heartvalve prostheses. It has been shown that bacterially synthesizedcellulose is particularly suitable for these purposes.

General Procedure for Producing a Molded Body from Storable andSwellable Bacterial Cellulose

It is known that bacteria of the species Gluconacetobacter xylinus candeposit cellulose on gas-permeable silicone membranes by metabolizingglucose-containing nutritive media. The depositing preferably takesplace on the silicone membrane. The silicone membrane can be configuredas a flat substrate, for example, or in the form of a three-dimensionalhollow body, in order to produce the cellulose in the shape of a tube,for example.

The silicone membrane is modified in a particular manner in order toproduce cellulose layers having different material thicknesses, in orderto prevent tension peaks at critical points in the event of strongmaterial loading, for example. In the production of heart valves it canbe advantageous, for example, to produce the valve leaflet requiredtherefor such that more material is present in the regions of highestmechanical load than in regions having a lower mechanical load. This canbe achieved by using a modified silicone membrane, the thickness ofwhich varies. In this manner it is possible to control the diffusion ofoxygen as a function of the layer thickness. Due to the reduced oxygenconcentration in the regions of the thicker silicone membrane, thelocally present bacteria can only produce cellulose to a lesser extent,while material is deposited to a greater extent in regions of thesilicone membrane having a thin layer thickness.

FIG. 9 presents a schematic illustration of a culture vessel 10, whichis suitable for producing cellulose layers 12 having differentthicknesses. According to one embodiment, 150 ml of a Hestrin/Schrammnutritive solution 14 are placed in the flat culture vessel 10 and areinoculated with 4 ml of an inoculation medium (Gluconacetobacterxylinus). The culture vessel 10 is covered with a gas-permeable siliconemembrane 16 without enclosing air. The culture vessel 10 is placed in anoxygen-enriched atmosphere in order to promote the aerobic growth of thebacteria on the silicone membrane 16. During incubation at 30° C. forseveral days, a cellulose layer 12 becomes deposited, which has thegreatest layer thickness at the point where the silicone membrane 16 isthe thinnest. Depending on the layer thickness of the silicone membrane16 and the incubation period, layer thicknesses of the cellulose layer12 in the range of 2 to 10 mm or more can be generated.

In general, the control of the layer thickness of the cellulose layer 12allows a design of layers which have a predetermined thickness. Thepredetermined thickness can be set to such an extent that workingmethods such as cutting, milling or laser ablation preferably of frozenor freeze dried cellulose can be applied to the material with a greaterflexibility than, for example, to biological material, which issignificantly thinner and requires a very precise handling and cuttingwhich is technically difficult to implement. Consequently the control oflayer thickness is advantageous in terms of a high accuracy of fit,stability and flexibility of the bacterial cellulose layer 12.

Furthermore, the thickness of the silicone membrane 16 can be variedacross its whole part in order to control not only the thickness of thebacterial cellulose layer 12, but also the form of the molded body. Withother words, the form of the silicone membrane can be used to controlthe thickness of the molded body in different sections. By varying thethickness in different parts the silicone membrane 16 the celluloseproduction of the bacteria can be controlled. It will be stronger inpositions where the silicone membrane has a lower thickness, and weakerwhere the silicone membrane has a higher thickness. Consequently, if acertain form of the silicone membrane 16 is provided, the molded bodywill have a corresponding reversed form.

Thus, the silicone membrane can be used as a positive image for the formof the cellulose body, so that the molded form presents a negative imageof the form of the silicone membrane 16. This way the design of thesilicone membrane 16 can be advantageously used to control the form ofthe molded body. Consequently a desired form of an implant comprisingbacterial cellulose, or at least of a part of it, can be designed by wayof controlled bacterial growth.

Composition of the Herstrin/Schramm Nutritive Solution:

Disodium hydrogen phosphate 2.7 g

Glucose 20 g

Soybean peptone 5 g

Yeast extract 5 g

Citric acid 1.15 g

Water 1 l

pH 6.0

A culture vessel according to the initially described embodiment of theinvention permits targeted control of the molded body made of bacterialcellulose. Given that the thickness can be varied in a targeted manneras described above, it is possible to produce inhomogenous molded bodiesas needed. These can be flexible sheets of a heart valve prosthesis, forexample. The zones having high mechanical load, where the sheets arefastened on the support body of the prosthesis or on a sealing skirt,can be made thicker and are therefore more highly loadable. By contrast,the flexible ends of the sheets are made thinner.

A further application of the molded bodies made of bacterial celluloseis that of artificial tendons. Optionally, the bacterial cellulose canalso be processed to form a composite material by admixing furthermaterials, for example polyacrylates, polyesters, polyamides,polyurethanes, polylactates, chitosan, and starch-containing plastics.

The cellulose layers 12 that form are washed with water and aresubsequently washed in a non-pyrogenic manner in an alkaline cleaningsolution. For the case in which the cellulose should have high strengthbut low swelling capacity, the cleaned cellulose layers 12 aremechanically pressed to a layer thickness of 0.07 to 0.1 mm. The layersare subsequently air-dried. These layers are incubated in a mixture of20% by weight of glycerol, 20% by weight of water, and 60% by weight ofisopropanol for 1 to 3 h and are subsequently mounted in a support frameand are dried.

The cellulose can be processed and stored in the dry state withoutlosing the positive characteristics thereof. The anti-inflammatoryproperties and the very good biocompatibility are retained, as is thehigh mechanical strength of the material.

The particular swelling capacity of the non-pressed but treatedbacterial cellulose was investigated more closely using 2 mm-thicklayers of the material. The samples were initially completely hydratedin water (12 h) and weighed. The samples were then incubated in anincubation mixture comprising, for example, 30% by weight of glyceroland 56% by weight of an C1-C3 alcohol and 14% by weight of water for 2h, removed, air-dried for 24 h, and weighed. Next, the samples wererehydrated in water for 12 h and weighed. The additional water uptake,in percent, compared to the non-treated material is presented in thefinal column of table 1.

Sample Hydrated (mg) Dry (mg) Rehydrated (mg) % 1 804 136 1000 124.3 2746 138 956 128.1 3 681 116 834 122.4 4 793 131 922 116.2 5 797 126 827103.7 6 755 125 843 111.6 7 732 127 874 119.3 8 771 112 874 113.3 9 686108 768 111.9 10 627 123 720 114.8 11 678 143 848 125.0 12 738 111 1140154.4 13 617 122 761 123.3 14 695 127 977 140.5 15 726 127 877 120.7Mean 723 124.8 881.4 122

It is evident that the swelling capacity was significantly increasedunder the aforementioned experimental conditions.

The treated cellulose was investigated in an in vitro assay in order toinvestigate the anti-inflammatory properties (see FIG. 10). A titaniumsurface (labelled “Ti” in the graph), which often used in pacemakers,was used as the reference value. The activation of the cells in theabsence of titanium (cells alone) or the treated cellulose (cm) wasmeasured as the reference value. To this end, the corresponding surfaceswere cultivated in a special sample chamber together with mononuclearcells (THP-1 cells), which indicate the activity status of NF-kB, aninflammatory marker. Each test series was carried out in triplicate. Thecells were additionally activated with LPS (lipopolysaccharide), therebysimulating an inflammatory reaction (the bar on the right in each case).Next, the activation of NF-kB was quantitatively evaluated. The NF-kBactivation of the THP-1 cells in the presence of the treated cellulose(18 a.u.) was found to be clearly reduced as compared to the titaniumsurface (28 a.u.). In this case, the NF-kB activation by the treatedcellulose is just as great as the negative control. This illustratesonce more that the treated cellulose has a very mild effect on the NF-kBactivation of the THP-1 cells and, therefore, inflammatory reactions arepractically unexpected. The treated cellulose will therefore likely onlytrigger a greatly diminished immune response in the human body and theimmunologically active cells will retain their immunocompetence.

A few specific applications of the treated bacterial cellulose aredescribed in the following.

Implant Shell for a Cardiac Pacemaker

According to this embodiment, an implant shell 20 was produced from thetreated bacterial cellulose, and was used to accommodate a cardiacpacemaker 22 (see FIG. 1).

In accordance with the above-described general procedure, three layersof bacterial cellulose each having a layer thickness of 0.2 mm weredried. The layers were sutured to one another to form the implant shell20, using a polymer thread (PTFE, size 5-0) and a 0.3 mm suture needle,using a shell scalloping stitch. The thusly sutured implant shell 20made of cellulose can be sterilized and stored in the dry state.

The pacemaker 22, with the electrodes attached, is rehydrated andpackaged by means of a sterile (isotonic) saline solution shortly beforeimplantation. FIG. 1 shows—in a highly schematic depiction—the completedimplant shell 20 in a top view, said implant shell being used toaccommodate the pacemaker 22. The direction of insertion is indicated bythe arrow.

The overhanging electrodes are wound up in a separate pocket 24 of theimplant shell 20.

Transcatheter Heart Valve Prosthesis

According to this embodiment, components of a transcatheter heart valveprosthesis were produced from the treated cellulose.

The cardiac septum separates the human heart into two halves, i.e. intoa right ventricle and a right atrium, and into a left ventricle and aleft atrium. Four heart valves are located between the ventricles andthe atria. Blood that is anoxemic but rich in carbon dioxide flows firstthrough the tricuspid valve into the right atrium and, from there, intothe right ventricle. The tricuspid valve is a tricuspidate valve and isalso referred to as an atrioventricular valve. From the right chamber,blood flows through the pulmonary valve into both lungs, where the bloodis re-enriched with oxygen. The pulmonary valve is a so-called semilunarvalve. The oxygen-enriched blood now leaves the lungs, enters the leftatrium, and is pumped through the mitral valve, which has the form of abicuspidate atrioventricular valve, into the left chamber.

Finally, the blood flows out of the left ventricle, through the aorticvalve, and into major blood circulation. The aortic valve, similar tothe pulmonary valve, is a semilunar valve.

If a patient has heart valve defects, it can be assumed that thefunctionality of these heart valves can worsen continuously over time.The replacement of heart valves that have stopped functioning with heartvalve prostheses has since become second only to the coronary bypassoperation as the most common operation performed on the human heart. Anideal heart valve replacement should have an unlimited service life,should allow blood to flow unobstructed in the vessel, should not resultin heart valve-related complications such as increased thrombogenicityor susceptibility to endocarditis, should not pose any risks inherent toprostheses, such as valve-related defects, should permit easyimplantation, and should be quiet.

Minimally invasive techniques and transcatheter heart valve prostheseshave since been developed, in which the new heart valve is brought tothe implantation site by means of a catheter system and is anchoredthere. The anchoring in the vessel wall is implemented by means of asupport structure for the actual heart valve, for example by means of ametallic mesh having a design and material selection similar to that ofa stent, which is therefore also referred to in the following as a stentbase body. The stent base body can be self-expanding, or can be expandedusing a balloon catheter.

Conventional transcatheter heart valve prostheses therefore comprise astent base body, which can be expanded from a first size, which isconfigured for minimally invasive insertion, into a functional, secondsize. The actual heart valve is fixed on this support structure, whereinsaid heart valve initially assumes a first shape, which is configuredfor minimally invasive insertion and which can be expanded, over thecourse of implantation, into the functional, second shape. For example,the heart valve is formed of a plurality of flexible sheets, each ofwhich opens or closes according to the bloodflow forces acting thereon.Such a transcatheter heart valve prosthesis comprising a biologicalcardiac valve is described in EP 1 267 753 B1, for example.

A schematic side view of an expanded transcatheter heart valveprosthesis 30 is shown in FIG. 2. The embodiment depicted in FIG. 2 is aheart valve prosthesis that is intended for implantation as areplacement of the natural mitral valve. The stent base body 32comprising metallic struts is used for anchoring at the implantationsite. In this case, a peripheral sealing shell (also referred to as theskirt 34) made of the treated bacterial cellulose is fastened on thestent base body 32 by means of suturing (over-and-over sutures 35 ofTeflon thread, for example), wherein said sealing shell is adjoinedhere, without transition, by the cardiac valve leaflets 38 (see FIG. 3),which are made of the same material. In order to build this complexmolded body comprising the skirt 34 and the cardiac valve leaflets 38,cellulose layers that have been dried according to the above-describedsynthesis procedure are cut to fit. A strip of the swellable cellulosematerial that is approximately 1.5 mm wide and approximately 0.2 mmthick is used for the skirt 34. After implantation and contact withblood, the thickness of the skirt 34 increases multifold (up to 0.5 mm)and seals the contour of the annulus 39, which is non-uniform due to thecalcified natural valve. The heart valve prosthesis is then mounted on acatheter and sterilized.

FIG. 4 shows a partial view of a structure of a stent base body withstruts 3 a, 3 b, 3 c, and 3 d. The adjacent struts 3 a, 3 b, 3 c, 3 dare connected via a nodal point 4. The stent struts form a rhombus-likeopening. This stent structure can be advantageously used for disposingstrips of bacterial cellulose in an interwoven pattern. The strips canbe sewn to each other and/or to the stents. In one embodiment, as shownin FIG. 5, the strips are passed over and under the nodal points 4.Thereby a first surface 7 a is formed, which is located above the stentstruts 3 a, 3 b, 3 c, 3 d and the nodal points 4, and a second surface 7b, which is located below the named struts and nodal points. Thebacterial cellulose can be treated by mechanical pressing in such a waythat the sections of the material below the named struts and nodalpoints have a reduced swelling capacity. Furthermore the strips ofcellulose can be disposed in such a way that the edges of the strips areoverlapping each other for a small part, which is indicated by thedashed lines. The overlapping is advantageous because it helpspreventing a flow through.

FIG. 6 shows a further embodiment wherein the strips are interweavedinto the stent structure by passing a first strip 5 a above and belowthe struts 3 a and 3 c and a second strip 5 b above and below the struts3 b and 3 d. Struts below the cellulose are shown as dashed lines,struts above the cellulose are shown as thick lines. As in FIG. 5,surfaces 7 a and 7 b of the stripes are shown which are located aboveand below the stent structure, respectively. The interweaving of thebacterial cellulose in the stent structure results in a constantalternation of the surfaces 7 a and 7 b.

In the case of a mitral valve prosthesis, small barbs 36 (having alength of approximately 0.1 to 0.3 mm) are optionally mounted on theouter strut surface on the stent base body 32, as shown in FIG. 11, in atop and side view of sections of a strut. These barbs are configuredsuch that they do not affect the sutures 35 required to produce thevalve. Since a large number of these small barbs 36 can be mounted onthe outer side, the adhesive connection for preventing dislocation ofthe valve is ensured. The barbs 36 can be mounted on the entire outerside, in particular in the region of the mitral annulus and the nativevalve cusps. As a result, the retaining force can be distributed aroundthe entire circumferential length of the valve. In order to produce thebarbs 36, an electropolished stent base body can be drawn on a steelmandrel and the outer surface of the struts can be provided with barbs36 by means of necking tools.

In order to ensure that the crimped stent can unfold nevertheless, thesebarbs can be covered with a biocompatible and rapidly dissolvablematerial, which temporarily covers the barbs 36.

The material dissolves in the bloodstream within seconds to minutesafter the stent base body is unfolded. Materials that are suitabletherefor are completely hydrolyzed, low- to medium-molecular polyvinylalcohol or hydrolyzed silk protein, for example.

The valve cusps 38 are produced from the cellulose, which has beenpretreated by means of mechanical pressing. The valve cusps 38 and theskirt 34 are sutured to one another or are already a component of acommon formed body. In the latter case, only the sections of the commonformed body that are intended to form the valve cusps 38 are pretreatedby mechanical pressing according to step ii) of the method. Themechanical loadability of bacterial cellulose can be decisivelyincreased by means of a variable layer thickness. For example, a heartvalve constructed of bacterial cellulose can have an increased materialthickness at the commissures, while the material at the free ends of thevalve cusps can be configured to be thinner and, therefore, bettercapable of moving. As a result, mechanical loads at the commissures areweakened, without limiting the valve movement to an excessive extent.This is not possible, in particular, when porcine or bovine pericardiumis used. In this case, the valve cusps have homogeneous layerthicknesses, which can result in mechanical overloading at the seams.

Since the material can be processed and stored in the dry state, andsince the material can be produced in different layer thicknesses, withdifferent swelling capacities and mechanical strengths, it is possibleto construct the entire transcatheter heart valve prosthesis, forexample a transcutaneous aortic valve, out of bacterial cellulose.

The skirt 34 on the proximal end of the valve itself minimizes unwantedleakage flows. To this end, the specially treated cellulose of the skirt34 is sutured onto the proximal struts of the stent base body 32,wherein these have the property of swelling by absorbing water. Thisswelling induces a minimal proximal displacement of the stent base body32 in the direction of the atrium, and so, in the case of a mitralvalve, the barbs 36 finally engage in the surrounding native tissue. Inthe embodiment of a heart valve prosthesis for use as a mitral valvereplacement, a skirt is therefore installed in the proximal outflowregion of the heart valve prosthesis in order to prevent leakage flows.

An embodiment of the invention as a heart valve prosthesis for replacingthe natural aortic valve (not illustrated) is also advantageous. Such anembodiment is substantially similar to the embodiment of a heart valveprosthesis for use as a mitral valve replacement as shown in FIG. 2. Inthe case of a heart valve prosthesis for use as an aortic valvereplacement, the proximal part is the inflow region of the valve. Theopen and closed position of the valve cusp is correspondingly opposed tothe embodiment of a heart valve prosthesis for use as a mitral valvereplacement. Likewise, in the case of a heart valve prosthesis for useas an aortic valve replacement, a skirt made of swellable bacterialcellulose is advantageously disposed in the proximal region of thesupport stent in order to prevent leakage flows in the inflow region.

The valve cusps made of bacterial cellulose are fastened on the supportstent by means of the skirt and, optionally, can be configured such thatsaid valve cusps have a greater thickness and, therefore, greatermechanical stability in the region of the fastening on the skirt/supportstent than in the flexible region in the center of the flow channelformed by the heart valve prosthesis.

Stent Graft

According to this embodiment, an inner and/or outer shell of a stentgraft is produced from the specially treated bacterial cellulose (seeFIG. 7). A stent graft is the combination of a stabilizing supportframe, which is also referred to in the following as the stent basebody, and an artificial blood vessel (vascular prosthesis). Theimplantation of a stent graft is an endovascular operation. The stentgraft is used, in particular, in order to exclude aneurysms from thebloodstream. In the present case, the stent base body is provided withan inner shell made of treated cellulose.

As described above, tubes can be made from cellulose and can be treated.In this case, a microstructure can be impressed on the luminal side ofthe inner shell during the cellulose synthesis, because the fiberorientation of cellulose bacterially synthesized on the inner side ofsilicone tubes exhibits a preferred direction along the longitudinalaxis of the silicone tube.

This preferred direction can be further enhanced by providing thesilicone tube with longitudinal grooves on the inner side that have agroove spacing of 0.5 to 12 m, preferably 1 to 10 m and a groove depthof 2 to 5 m.

The stent base body 40 preferably self-expanding is fastened on theinner shell 44, which was produced using cellulose, by means of asurgical suture material 42. Strips 46, which are also tubular and havea width of 1 to 2 cm, are then fastened on the outer side at both endsby means of suturing. This strip 46 made of cellulose has a greaterswelling capacity as compared to the inner shell 44 and therefore makesit possible to seal leaky points after implantation withoutsubstantially increasing the diameter of the implant duringimplantation.

Vascular Patches

According to a further embodiment, the molded body made of the treatedcellulose is a vascular patch.

In medicine, a vascular patch is understood to be a piece of foreignmaterial that is used in surgical procedures to close an unwantedopening. A patch is always used whenever an opening cannot be closedwithout complications by means of a simple seam. One example of regularuse are heart surgeries in which septal defects, for example, are closedat this time by means of pericardial or PTFE patches. A patch is alsoused for the vascular surgical widening of a blood vessel (arterial andvenous) or for covering defects on the blood vessels. The patch issutured into the opened vessel, for example to prevent stenoses causedby seams, or for purposes of widening. In the present case, the patch isproduced of the bacterial cellulose treated in the above-describedmanner.

Covered Stent

According to a further embodiment, a stent is covered by a fleececomprising the treated bacterial cellulose (FIG. 8).

A stent (which is also referred to as a vascular support) is a medicalimplant that is inserted into hollow organs, in order to hold theseopen. The stent is usually a small lattice framework in the shape of asmall tube composed of metal or plastic fibers, which is also referredto as a stent base body in the present case. 150 ml Hestrin/Schrammnutritive solution having the aforementioned composition are placed in acylindrical culture vessel and are inoculated with 4 ml of aninoculation solution (Gluconacetobacter xylinus). A gas-permeablesilicone tube carrying, on the surface thereof, the stent base body tobe covered is hung in the culture vessel. The inner side of the tube isacted upon with pure oxygen in order to promote the aerobic growth ofthe bacteria on the silicone surface. Next, cultivation is allowed totake place at 30° C. until the necessary layer thickness is reached. Theobjective is to obtain a layer thickness of 2 to 5 mm. The celluloselayers that form are washed with water and are subsequently washed in anon-pyrogenic manner in an alkaline cleaning solution.

The purified cellulose fiber tubes are pressed to a layer thickness of0.07 to 0.1 mm by means of crimping. Next, the tubes are mounted on amandrel and are air-dried. These layers are incubated in a mixture of20% by weight of glycerol, 20% by weight of water, and 60% by is weightof isopropanol for 1 to 3 h and are subsequently mounted on a mandrelonce more and are dried.

FIG. 8 shows a schematic view of a stent 50 covered with bacterialcellulose, before drying (on the left) and after drying (on the right).The drying reduces the thickness of the cellulose layer 52 multifold.

It will be apparent to those skilled in the art that numerousmodifications and variations of the described examples and embodimentsare possible in light of the above teaching. The disclosed examples andembodiments are presented for purposes of illustration only. Otheralternate embodiments may include some or all of the features disclosedherein. Therefore, it is the intent to cover all such modifications andalternate embodiments as may come within the true scope of thisinvention.

1. A method for producing a storable and swellable molded body made ofbacterial cellulose, wherein the method comprises steps of: providing amolded body made of bacterial cellulose; treating the molded body with atreatment solution of 20% by weight to 50% by weight of glycerol and 50%by weight to 80% by weight of a C1-C3-alcohol/water mixture; and dryingthe treated molded body.
 2. The method according to claim 1, wherein thetreatment solution comprises a solution of 35% by weight to 75% byweight of C1-C3 alcohol 5% by weight to 25% by weight of water and20-50% by weight of glycerol.
 3. The method according to claim 1,wherein the treatment solution contains a water portion of at most 20%by weight.
 4. A storable molded body made of treated bacterialcellulose, wherein the treated bacterial cellulose is dry and has aswelling capacity that is greater than untreated bacterial cellulose ofthe same type.
 5. An implant comprising, entirely or in parts, themolded body according to claim
 4. 6. The implant according to claim 5,wherein the molded body is an implant shell.
 7. The implant according toclaim 6, wherein the implant is a cardiac pacemaker or a defibrillatorwhich is stored in the implant shell.
 8. The implant according to claim7, wherein the implant shell is a separate pocket for accommodatingelectrode cables.
 9. The implant according to claim 5, wherein themolded body is a heart valve leaflet and/or a sealing shell betweenheart valve leaflets of a heart valve prosthesis.
 10. The implantaccording to claim 9, wherein an outer side of a stent base body of theheart valve prosthesis comprises barbs.
 11. The implant according toclaim 5, wherein the molded body is an outer shell and/or inner shell ofa stent graft made of the implant material.
 12. The implant according toclaim 11, wherein the inner or outer shell comprises annular sections,which are disposed on the axial ends of the stent graft and exhibit agreater swelling capacity than do sections of the shells located betweenthe two ends.
 13. The implant according to claim 5, wherein the moldedbody is a coating of a stent.
 14. The implant according to claim 5,wherein the molded body is a vascular path, an occluder, or anartificial tendon.
 15. A catheter system for the insertion of an implantaccording to wherein the implant is mounted in the dried state on thecatheter.
 16. The method according to claim 1, further comprising, priorto said treating, mechanically pressing the entire molded body or partsof the molded body at temperatures in the range of 10° C. to 100° C. andpressures in the range of 0.01 to 1 MPa for a pressing time of 10-200min.
 17. The method according to claim 2, wherein the C1-C3 alcohol is2-propanol.
 18. The storable molded body according to claim 4, whereinthe swelling capacity of the treated bacterial cellulose is betweenabout 103% and 154% greater than the non-treated bacterial cellulose.